Skin care formulation

ABSTRACT

There is provided a skin care formulation for transdermal administration of a component of a blood product, the formulation comprising a blood product, a transdermal carrier; and a liposomal base, wherein at least a portion of the blood product and transdermal carrier is contained within liposomes of the liposomal base.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/306,361, filed on Nov. 30, 2018, which, in turn, is a 371continuation of PCT/AU/2017/000124 filed on Jun. 2, 2017, which, inturn, claims the benefit of U.S. Provisional Patent Application No.62/345,036, filed on 3 Jun. 2016 and U.S. Provisional Patent ApplicationNo. 62/369,240, filed on 1 Aug. 2016, the disclosures of all of whichare hereby expressly incorporated by reference in their entireties.

TECHNICAL FIELD

The technology relates to liposomal skin care formulations comprisingblood serum, plasma or components thereof contained within liposomes. Inparticular, the technology relates to liposomal skin care formulationsfor systemic application of a component of blood serum or plasma by atransdermal route.

BACKGROUND

Human skin is subject to deterioration due to numerous factors includingaging and dermatological disorders conditions or diseases such asdermatitis, psoriasis, eczma, pruritus, acne, rash, dryness andwounding. In addition, deterioration occurs from environmental factorssuch as from wind, air conditioning, and central heating, or through thenormal ageing process, which may be accelerated by exposure of skin tosun. In particular, ageing is characterized by the appearance ofwrinkles, variations in skin pigmentation and the loss of elasticity andcompactness.

The pathogenesis of skin ageing is characterized by a decrease incollagen synthesis and an increase in collagen breakdown. The loss ofdermal collagen is contributes to or facilitates wrinkling.

Alopecia (Hair loss, either complete or partial) affects both men andwomen but increases in prevalence as age increases. The hair lossprocess typically involves a process of follicular miniaturization, inwhich the cells in the hair follicle begin to deteriorate. onsequently,the hair's growth phase is shortened and hair is prevented from maturinginto the pigmented terminal hair typically seen on the head. Over timethe follicle goes dormant and ceases producing hair completely.

Numerous cosmetic and therapeutic skin care products are currentlyavailable for topical use to reduce the effects of skin ageing, skinconditions or hair loss. These typically comprise various chemicalcomponents, polymers, oils, antioxidants and the like.

It is believed that biological factors that stimulate collagenproduction and cell growth in wound healing might provide benefits forageing skin and hair loss and such factors, including growth factors,peptide fragments, and other biologically active molecules have beenincorporated into anti-aging cosmetics and therapeutics.

While the use of biological factors to treat aging skin is gaining favorthere remains an unmet need for effective topical formulations for theprevention and treatment of skin damage, wrinkles and other defectsassociated with aging or caused by environmental factors.

The present inventors have developed a formulation for transdermaldelivery of one or more components of a blood product such as plasma orserum.

SUMMARY

In a first aspect, there is provided a skin care formulation fortransdermal administration of a component of a blood product, theformulation comprising:

-   a blood product;

a transdermal carrier; and

a liposomal base;

wherein at least a portion of the blood product and transdermal carrieris contained within liposomes of the liposomal base.

The skin care formulation may be present in a nasal dosage form or anoral dosage form for transdermal delivery of the component of the bloodproduct. The oral dosage form may be selected from a sublingual troche,tablet, wafer or lozenge. In some embodiments the oral dosage form is abuccal troche, tablet, wafer, lozenge or orally disintegrating tablet.

In one embodiment the formulation may comprise a therapeuticallyeffective dose of a component of the blood product.

The formulation may additionally comprise an transdermal enhancer.

The blood product may be selected from plasma, serum, platelet richplasma, conditioned plasma, conditioned serum, and combinations thereof.

In some embodiments the conditioned serum is autologous conditionedserum .

The blood product may be derived from a subject of any age, for exampleand 18-25 year old, a 25-35 year old, a 35-45 year old, a 45-55 yearold, a 55-65 year old or a subject that is 65 or more years old.

The blood product may be derived from a placenta and/or an umbilicalcord.

The blood product may be a human blood product. In some embodiments theblood product may be pooled from a number of humans or produced fromblood pooled from a number of humans. The blood product may be from anumbilical cord, placenta or donated blood.

In some embodiments the blood product may comprise fragments ofregenerative cells. The regenerative cell fragments may be selected frommesenchymal stem cells, endothelial progenitor cells, hematopoietic stemcells, monocytes, macrophages, keratinocytes, and fibroblasts. The skincare formulation may include a blood product comprising fragments ofregenerative cells

The blood product may be lyophilized.

The component of serum or plasma may be a growth factor, cytokine,chemokine, hormone, vitamin, or cell fragment.

The growth factor may be selected from endothelial growth factor (EGF),hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF),granulocyte colony-stimulating factor (G-CSF), vascular endothelialgrowth factor (VEGF), transforming growth factor alpha (TGF-β), TGF-β1,TGF-β2, TGF-β3, platelet-derived growth factor (PDGF)-AA, PDGF-AB,PDGF-BB, insulin-like growth factor-1 (IGF-1), BMP, BDNF, EGF, HGF,PDGF,FGF, PGF, GDF-8, NGF, Epo, TPO, TCGF, IGF-I, IGF-II, KGF, VEGF, and anycombination thereof.

The cytokines may be pro-inflammatory or anti-inflammatory.

The pro-inflammatory cytokine may be for example granulocyte macrophagecolony-stimulating factor (GM-CSF), interleukin (IL)-1α, IL-1β, IL-2,IL-2R, IL-3, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-12p40/p70,IL-13, IL-14, IL-15, IL-17, tumour necrosis factor (TNF)α, TNF-β,interferon (IFN)-α, INF-β, INF-γ or any combination thereof.

The anti-inflammatory cytokine may be for example IL-1 RA, IL-4, IL-5,IL-10, IL-13, IFNα or any combination thereof.

The chemokine may be eotaxin, protein 10 (IP-10), monocytechemoattractant protein-1 (MCP-1), IFNγ-induced monokine, macrophageinflammatory protein (MIP)-1α, MIP-1β, RANTES or any combinationthereof.

The hormone may be selected from an amino acid hormone, eicosanoidhormone, a peptide hormone, and a steroid hormone.

The amino acid hormone may be selected from epinephrine, melatonin,triiodothyronine, and thyroxine.

The eicosanoid hormone may be selected from prostaglandins,leukotrienes, prostacyclin, and thromboxane.

The peptide hormone may be selected from amylin, anti-mullerian hormone,adiponectin, angiotensinogen, angiotensin, vasopressin, atrialnatriuretic peptide, brain natriuretic peptide, calcitonin,cholecystokin, corticotropin-releasing hormone, cortistatin, encephalin,endothelin, erythropoietin, galanin, gastric inhibitory peptide,gastrin, ghrelin, glucagon, glucagon-like-peptide-1,Gonadotropin-releasing hormone, Growth hormone-releasing hormone,hepcidin, Human chorionic gonadotropin, Human placental lactogen, humangrowth hormone, Inhibin, Insulin, Insulin-like growth factor, leptin,lipotropin, melanocyte stimulating hormone, motilin, orexin, oxytocin,pancreatic polypeptide, parathyroid hormone, pituitary adenylatecyclase-activating peptide, prolactin, prolactin releasing hormone,relaxin, renin, secretin, somatostatin, thrombopoietin,thyroid-stimulating hormone, and vasoactive intestinal peptide.

The steroid hormone may be selected from testosterone,dehydroepiandrosterone, androstenedione, dihydrotestosterone,aldosterone, estradiol, estrone, estriol, cortisol, progesterone,calcitriol, and calcidiol.

The liposomal base may be an emulsion that includes a lipophiliccomponent and an aqueous component. The liposomal base may be a lotion,a cream, a gel or a paste. Examples of suitable liposomal bases includePCCA Lipoderm®, Lipoderm ActiveMax™, Anhydrous Lipoderm and LipodermHigh Molecular Weight™ PCCA, Houston, Tex.

One example of a commercially available liposomal base suitable for usein the formulations provided herein includes, but is not limited to,Lipoderm® lipophilic liposome cream (a mixture of about 60-80% wt/wtwater, with glycerin, C12-15 alkyl benzoate, glyceryl stearate,dimethicone, cetearyl alcohol, cetearyl glucoside, polyacrylamide, cetylalcohol, magnesium aluminum silicate, xanthan gum, aloe vera (aloebarbadensis), tocopheryl acetate (vitamin E acetate), prunus amygadalusamara (bitter almond) kernel oil, vitis vinifera (Grape) seed extract,triticum vulgare (wheat) germ oil, retinyl palmitate (vitamin Apalmitate), ascorbyl palmitate (vitamin C palmitate), Pro-LipoMulti-emulsion Liposomic System, tetrasodium EDTA, phenoxyethanol,sodium hydroxymethylglycinate. PCCA, Houston, Tex.

The composition in LIPODERM™ lipophilic liposomic cream is particularlysuitable when formulated in accordance with the guidance providedherein. For example, the inventors have discovered that surprisingly, toformulate a composition that does not separate, it is important that theblood product be dissolved in a suitable mixed phase emulsion such asLIPODERM™.

The transdermal carrier may be selected from isopropyl alcohol,dipropylene glycol methyl-ether, butylated hydroxytoluene dipropyleneglycol monomethyl-ether, 1-methoxy 2-propanol (glysolv PM/Icinol PM),Ethylene glycol monobutylether (butyl glyxolv/butyl icinol), Butyl diglysolv (butyl-icinol), Transcutol, propylene glycol (PG), N-methyl-2pyrrolidone (NMP), methylene chloride, diethyl ether, ethanol,acetonitrile, ethyl acetate, benzyl alcohol, a combination of naturaloil; ethylene glycol, propylene glycol, dimethyl polysiloxane (DMPX),oleic acid, caprylic acid, 1-octanol, ethanol (denatured or anhydrous),liposomal compositions, suitable plant oils, such as Aloe veraderivatives or sesame seed oil or derivatives thereof, acrylic polymers,rubber-based polymers, polysiloxane-based polymers,polyvinylpyrrolidone-based polymers, dimethylsulfoxide (DMSO),dimethylformamide (DMF), lecithin, Transfersomes® (bi-componentvesicular aggregates), ethosomes, azone, castor oil derivatives, such asethoxylated castor oil, jojoba oil derivatives, corn oil derivatives,and emu oil derivatives.

In one embodiment the administration is systemic administration.

The transdermal carrier may be present in the formulation in an amountfrom about 1% (w/w) to about 50% (w/w). For example the transdermalcarrier may be present in the formulation at about 1% (w/w), about 2%(w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w),about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w), about11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15%(w/w), about 16% (w/w), about 17% (w/w), about 19% (w/w), about 20%(w/w), about 21% (w/w), about 22% (w/w), about 23% (w/w), about 24%(w/w), about 25% (w/w), about 26% (w/w), about 27% (w/w), about 28%(w/w), about 29% (w/w), about 30% (w/w), about 31% (w/w), about 32%(w/w), about 33% (w/w), about 34% (w/w), about 35% (w/w), about 36%(w/w), about 37% (w/w), about 38% (w/w), about 39% (w/w), about 40%(w/w), about 41% (w/w), about 42% (w/w), about 43% (w/w), about 44%(w/w), about 45% (w/w), about 46% (w/w), about 47% (w/w), about 48%(w/w), about 49% (w/w), or about 50% (w/w).

The transdermal enhancer may be present in the formulation in an amountfrom amount from about 1% (w/w) to about 30% (w/w). For example thetransdermal carrier may be present in the formulation at about 1% (w/w),about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6%(w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w),about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w),about 15% (w/w), about 16% (w/w), about 17% (w/w), about 19% (w/w),about 20% (w/w), about 21% (w/w), about 22% (w/w), about 23% (w/w),about 24% (w/w), about 25% (w/w), about 26% (w/w), about 27% (w/w),about 28% (w/w), about 29% (w/w) or about 30% (w/w).

In an embodiment the formulation comprises:

-   -   1% to 80% (v/w) of the blood product;    -   1% to 50% (w/w) of the transdermal carrier; and    -   up to 80% (w/w) of the liposomal base.

For example the blood product can be present in the formulation in anamount from about 1% to about 80% (w/w) or (v/w). For example the bloodproduct can be present in the formulation in an amount of about 1%,about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%,about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about15%, about 16%, about 17%, about 19%, about 20%, about 21%, about 22%,about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%,about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%,about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%,about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%,about 75%, about 76%, about 77%, about 78%, about 79%, or about 80%.

The transdermal carrier may be present in the formulation in an amountfrom about 1% (w/w) to about 50% (w/w). For example the transdermalcarrier may be present in the formulation at about 1% (w/w), about 2%(w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w),about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w), about11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15%(w/w), about 16% (w/w), about 17% (w/w), about 19% (w/w), about 20%(w/w), about 21% (w/w), about 22% (w/w), about 23% (w/w), about 24%(w/w), about 25% (w/w), about 26% (w/w), about 27% (w/w), about 28%(w/w), about 29% (w/w), about 30% (w/w), about 31% (w/w), about 32%(w/w), about 33% (w/w), about 34% (w/w), about 35% (w/w), about 36%(w/w), about 37% (w/w), about 38% (w/w), about 39% (w/w), about 40%(w/w), about 41% (w/w), about 42% (w/w), about 43% (w/w), about 44%(w/w), about 45% (w/w), about 46% (w/w), about 47% (w/w), about 48%(w/w), about 49% (w/w), or about 50% (w/w).

The liposomal base may be present in the formulation in any amount. Forexample the base may be present in the formulation in an amount of about1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5%(w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w)about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w),about 14% (w/w), about 15% (w/w), about 16% (w/w), about 17% (w/w),about 19% (w/w), about 20% (w/w), about 21% (w/w), about 22% (w/w),about 23% (w/w), about 24% (w/w), about 25% (w/w), about 26% (w/w),about 27% (w/w), about 28% (w/w), about 29% (w/w), about 30% (w/w),about 31% (w/w), about 32% (w/w), about 33% (w/w), about 34% (w/w),about 35% (w/w), about 36% (w/w), about 37% (w/w), about 38% (w/w),about 39% (w/w), about 40% (w/w), about 41% (w/w), about 42% (w/w),about 43% (w/w), about 44% (w/w), about 45% (w/w), about 46% (w/w),about 47% (w/w), about 48% (w/w), about 49% (w/w), about 50% (w/w),about 51% (w/w), about 52% (w/w), about 53% (w/w), about 54% (w/w),about 55% (w/w), about 56% (w/w), about 50% (w/w), about 58% (w/w),about 59% (w/w), about 60% (w/w), about 61% (w/w), about 62% (w/w),about 63% (w/w), about 64% (w/w), about 65% (w/w), about 66% (w/w),about 67% (w/w), about 68% (w/w), about 69% (w/w), about 70% (w/w),about 71% (w/w), about 72% (w/w), about 73% (w/w), about 74% (w/w),about 75% (w/w), about 76% (w/w), about 77% (w/w), about 78% (w/w),about 79% (w/w), or about 80% (w/w).

In an embodiment the blood product is Human plasma or plasma lysate,Human serum, Human PRP (platelet rich plasma), or Human Autologousconditioned serum; the transdermal carrier is Propylene Glycol; and theLiposomal base is PCCA Lipoderm® q.s.

In a second aspect there is provided a method of treating, preventing orameliorating a symptom or sign of a skin defect comprising: topicallyadministering to the skin of a subject in need thereof a formulation ofthe first aspect in an amount sufficient to treat, prevent or amelioratea symptom or sign of the skin defect.

The formulation may be administered at least once per day. For examplethe formulation may be administered may be applied daily, twice daily,three times or more than three times daily.

Application of the formula may be continued until the skin defect isresolved or prevented or until at least one symptom or sign of the skindefect is ameliorated. For example the formulation may be applied over aperiod of one week, two weeks, three weeks, four weeks, five weeks, sixweeks, seven weeks, eight weeks, nine weeks, ten weeks, twelve weeks orlonger.

The skin defect may be selected from poor skin texture, wrinkles, finelines, UV induced skin damage, skin aging, dry skin, hair follicledeterioration, alopecia, dermatitis, eczma, rash, pruritus, sun burn,burns, stretch marks, acne scars, and surgical scars.

The treatment may reduce the number of wrinkles or fine lines by about5%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45% or at least about 50% comparedto the number of wrinkles or fine lines before treatment.

Throughout this specification, unless the context requires otherwise,the word “comprise”, or variations such as “comprises” or “comprising”,will be understood to imply the inclusion of a stated element, integeror step, or group of elements, integers or steps, but not the exclusionof any other element, integer or step, or group of elements, integers orsteps.

Any discussion of documents, acts, materials, devices, articles or thelike which has been included in the present specification is solely forthe purpose of providing a context for the present invention. It is notto be taken as an admission that any or all of these matters form partof the prior art base or were common general knowledge in the fieldrelevant to the present invention as it existed before the priority dateof each claim of this specification.

Description

The present inventors have developed a topically applied formulation fortransdermal delivery of one or more components of a blood product suchas blood serum or blood plasma. In some embodiments the component issystemically administered via the transdermal route.

The formulations include three components: a liposomal base, a bloodproduct and a transdermal carrier.

The blood product in the formulation is present in the aqueous and/orlipophilic portions but is also encapsulated in liposomes of the base.The liposomes have a lipophilic membrane surrounding an aqueous interiorcompartment. The structure of the liposomes may include multilamellar orunilamellar liposomes or unstructured liposomal aggregates and/orcombinations of the same. A portion of the blood product is present inthe aqueous compartments of the liposome.

The formulations described herein are useful for preventing, reducingand/or eliminating skin defects such as poor skin texture, wrinkles,frown lines, UV induced skin damage, skin ageing, dry skin, hairfollicle deterioration, alopecia, dermatitis, eczema, rash, psoriasispruritus, sun burn, burns, stretch marks, acne scars and surgical scars(wound healing). Accordingly, the formulations may be used as analternative or in addition to cosmetic surgery, injectable cosmetictreatments such as fillers (Hyaluronic Acid) BOTOX®, silicone or otherproducts.

Skin ageing is a complex process characterized by decreased in collagensynthesis and increased collagen degradation. A number of growth factorsstimulate collagen production. In some embodiments the blood productsused in the formulations contain growth and/or inflammatory mediatorssuch as, for example, PDGF, IGFs, FGFs, TGFs, EGF, VEGF, HGF, IL-6,G-SCF and KGF as well as extracellular matrix proteins such as type Iand type III collagens, fibronectin, terascin, glycosaminoglycans,versican, decorin and other secreted dermal matrix proteins, which maybe useful in preventing or repairing skin defects. In addition peptidessuch as KTTKS and palmitoyl-KTTKS, which promote collagen synthesis, andargireline, a synthetic peptide that inhibits muscle-induced wrinklingof the skin, may also be added to the formulation.

The formulations may include one of more of the following general typesof ingredients:

-   -   Emollients: for example plant oils, mineral oils, shea butter,        cocoa butter, petrolatum, cholesterol, silicones or animal oils        (including emu, mink and lanolin). These emollients contribute        to softening and smoothing the skin while functioning to assist        in moisture retention. In some embodiments, jojoba, squalene and        lanolin are used because of their similarity to and are the        least comedogenic (pore-clogging).    -   Humectants: for example sorbitol, glycols, glycerins and sodium        PCA. Humectants act to attract water to the skin and are        desirable inclusions in the formulations for applications of the        formulations to treat/prevent skin damaged by sun and        dehydration.    -   Soothing agents and anti-irritants: for example bisabolol,        allantoin, burdock root, aloe, licorice root, glycyrrhetinic        acid, green tea and chamomile extract, may be added to the        formulations.    -   Vitamins and antioxidants: for example vitamins A, B group (in        particular vitamins B3, B5 and B9), C and E.    -   Alpha hydroxy acids (AHAs) and beta hydroxy acids (BHAs): these        compounds are believed to be useful to clear pores and remove        dead skin thereby promoting smoother, moister skin. Examples of        useful AHAs formulations include glycolic acid and lactic acid,        fruit or citrus acid, and sugarcane extracts. Examples of a        useful BHA is salicylic acid. AHA increases sun sensitivity and        so formulations containing AHA typically also include physical        and/or chemical sunscreen agents.    -   Antioxidants: Suitable antioxidants include ascorbic acid,        sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium        thiosulfite, sodium formaldehyde sulfoxylate, isoascorbic acid,        thioglycerol, thiosorbitol, thiourea, thioglycolic acid,        cysteine hydrochloride, 1,4-diazobicyclo-(2,2,2)-octane,        butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated        hydroxyanisole, a-tocopherol, phenyl-a-naphthylamine, and        mixtures thereof; and    -   Polysaccharides such as glucomannan or guar gum.

In one embodiment the formulation comprises hyaluronic acid (HA) or asalt thereof. The HA or salt thereof may be present in an amount of 0.1%to 10% by weight of the formulation. For example the For example the HAor salt thereof may be present in the formulation at about 0.1% (w/w),about 0.5% (w/w), about 1% (w/w), about 2% (w/w), about 3% (w/w), about4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8%(w/w), about 9% (w/w) or about 10% (w/w).

The formulations are topically applied to a subject for example byrubbing, smearing or massaging into an area of skin.

Assays commonly employed by those of skill in the art may be utilized totest the activity of the particular components, thereby ensuring that anacceptable level of biological activity (e.g., a therapeuticallyeffective amount) is retained. Doses of such therapeutic factors arewell known to those of skill in the art and may be found inpharmaceutical compendia such as the Physicians' Desk Reference, MedicalEconomics Data Publishers; Remington's Pharmaceutical Sciences, MackPublishing Co.; Goodman & Gilman, The Pharmacological Basis OfTherapeutics, McGraw Hill Publ.

The effective doses of any of the components described herein mayroutinely be determined using techniques well known to those of skill inthe art. A “therapeutically effective” dose refers to that amount of thecomponent sufficient to result in amelioration of at least one sign orsymptom of skin defect.

The formulations can have a pH of about 6 to about 9, in someembodiments the pH is from 6.0 to 7.0. In other embodiments the pH canbe 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.

In some embodiments the formulations have UVA and UVB absorptionproperties. In these embodiments, the formulations have a sun protectionfactor (SPF) of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25,30, 35, 40, 45, 50, 55, 60, or more, or any integer or derivativetherein. The formulation may comprise any UVA and UVB absorbing compoundknown in the art. For example the formulation may comprise oxybenzone,avobenzone, octisalate, octocrylene, homosalate, octinoxate, zinc oxidetitanium dioxide or any combination thereof.

The formulation is applied topically and can be prepared in the form ofa hand or body cream, hair shampoo, under eye cream, bath gel or soap,shaving or after shaving lotion. These forms can be prepared using theformulations described herein in conjunction within methods known in theart.

The formulations can provide systemic delivery via a transdermal routeof at least one component of the blood product. The component crossesthe skin and enters the circulation (for example the blood or lymph) andis distributed substantially throughout the body (i.e. systemically).Accordingly, while the effect of the formulation will be observable atthe site of administration (for example a portion of the skin) theeffects will also be observable at sites distal to the site ofadministration due to the systemic delivery of one or more components ofthe blood product.

Liposomal Base

Any suitable liposomal base known in the art may be used in theformulations provided herein. Typically the liposomal base is anemulsion that includes a lipophilic component and an aqueous componentthat are emulsified such that the lipophilic component forms liposomescontaining a portion of the aqueous component.

The liposomal base may take any form. For example the liposomal base maybe a lotion, a cream, a gel or a paste. Preferably the liposomal base isa lotion or a cream.

One example of a commercially available liposomal base suitable for usein the formulations provided herein includes, but is not limited to,LIPODERM™ cream or gel (a mixture of about 60-80% wt/wt water, withglycerin, C12-15 alkyl benzoate, glyceryl stearate, dimethicone,cetearyl alcohol, cetearyl glucoside, polyacrylamide, cetyl alcohol,magnesium aluminum silicate, xanthan gum, aloe vera (aloe barbadensis),tocopheryl acetate (vitamin E acetate), prunus amygadalus amara (bitteralmond) kernel oil, vitis vinifera (Grape) seed extract, triticumvulgare (wheat) germ oil, retinyl palmitate (vitamin A palmitate),ascorbyl palmitate (vitamin C palmitate), Pro-Lipo Multi-emulsionLiposomic System, tetrasodium EDTA, phenoxyethanol, sodiumhydroxymethylglycinate). PCCA, Houston, Tex.

Other suitable liposomal bases include, but are not limited to,DEMI-GEL™ emulsion (which is a mixture of 4% lecithin isopropylpalmitate containing lecithin soya granular, isopropyl palmitate NF,sorbic acid NF).

Although use of commercially available liposomal bases, gels anddiluents is convenient the formulations provided herein may be preparedwith any suitable emulsion.

Blood Products

The formulations described herein contain a blood product. Typically theblood product is serum, plasma or platelet rich plasma (plasma lysate,autologous conditioned serum). However any blood product known in theart may be used in the formulations.

The source of the blood product may be umbilical cord blood or bloodretrieved from a placenta from a normal or C-section childbirthdelivery. Alternatively or in addition the source of the blood for theblood product blood donated to blood banks or from frozen cord bloodunits stored in public or family cord blood banks. The source of theblood for the blood product may be from the patient's own blood.

The blood product may be pooled from a number of donors. For exampleblood from individual donors may be typed, cross-matched or both andpooled according to type and or cross-matching characteristics beforepreparation of a blood product from the pooled samples. The blood may bepooled from adult donors or from umbilical cords or placentas.

The blood product may comprise fragments of regenerative cells orproducts from regenerative cells. The term regenerative cells refers toany one or combination (in any proportion) of mesenchymal stem cells,progenitor cells, hematopoietic stem and progenitor cells, monocytes,macrophages, keratinocytes, fibroblasts, and any other cell type,excluding embryonic stem cells, that produces or secretes growthfactors, hormones, cytokines or regulatory factors. The fragments ofregenerative cells or products thereof may naturally be present in theblood product or may be added from an exogenous source (for example fromcultured cells). The regenerative cells may be selected from the groupconsisting of mesenchymal stem cells, endothelial progenitor cells,hematopoietic stem cells, monocytes, macrophages, keratinocytes andfibroblasts. When added from an exogenous source the regenerative cellsmay be used immediately or after being frozen for a time. In embodimentswhere regenerative cells are donated they may be used immediately orafter being frozen for a time.

In some embodiments the blood product is lyophilised (also known asfreeze drying or cryodesiccation) prior to incorporation into theformulation. Lyophilisation can be achieved by any means known in theart and typically includes four steps, pre-treatment, freezing, primaryand secondary drying. The pre-treatment step may include concentratingthe blood product, the addition of stability enhancers or preservativesor increasing the surface area of the blood product.

In the second step (freezing) the blood product is cooled to below itstriple point (the lowest temperature at which the solid and liquidphases coexist) in order to ensure that sublimation occurs in the dryingsteps. In some embodiments the freezing step includes annealing in whichthe temperature is reportedly raised and lowered. In other embodimentsfreezing is done as rapidly as practical to lower the blood product tobelow its eutectic point quickly to avoid ice crystal formation.Usually, the freezing temperatures are between −30° C. and −80° C.

During primary drying the pressure is lowered and enough heat issupplied to the blood product for the ice to sublime. The amount of heatnecessary can be calculated by a skilled person with consideration ofthe blood products latent heat of sublimation. Pressure on the bloodproduct is controlled through the application of partial vacuum.Application of a vacuum increases the rate of sublimation. In theprimary drying phase about 90-95% of the water in the blood product issublimated.

The secondary drying phase removes unfrozen water from the blood productand is dependent on the blood product's adsorption isotherms. Thetemperature is raised higher than in the primary drying phase, and caneven be above 0° C. in order to break physicochemical interactionsbetween water molecules and frozen material in the blood product. Insome embodiments the pressure on the blood product is further decreasedto facilitate desorption of water. The residual water content of theblood product is around 1% to 5%, for example 0.5%, 1%, 1.5%, 2.0%,2.5%, 3.0%, 3.5%, 4.0%, 4.5% or about 5%.

The blood product can be present in a formulation in an amount fromabout 1% to about 80% (w/w) or (v/w). For example the blood product canbe present in a formulation in an amount of about 1%, about 2%, about3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,about 17%, about 19%, about 20%, about 21%, about 22%, about 23%, about24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%,about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%,about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%,about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%,about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about76%, about 77%, about 78%, about 79%, or about 80%.

The blood product may contain one or more components such asmetabolites, amino acids, proteins, growth factors, hormones, traceelements, vitamins and minerals.

For example the blood product component may be selected fromacetoacetate, acetone, acetylcholine, adenosine triphosphate,adrenocorticotrophic hormone, alanine, albumin, aluminum, aldosterone,amino acids, alpha-aminobutyric acid, d-aminolevulinic acid, ammonianitrogen, cAMP, androstenedione, androsterone, angiotensin I,angiotensin II, alpha 1-antitrypsin, arginine, arsenic, ascorbic acid(vitamin C), aspartic acid, aspartic acid (in WBCs), bicarbonate, bileacids, bilirubin, biotin (vitamin H), bradykinin, bromide, cadmium,calciferol (vitamin D2), calcitonin (CT), calcium, carbon dioxide,carboxyhemoglobin (as HbCO), carcinoembryonic antigen, beta-carotene,carotenoids, cephalin, ceruloplasmin, cholecalciferol (vitamin D3),cholecystokinin (pancreozymin), cholesterol, choline, chorionicgonadotropin, citric acid, citrulline, coagulation factors (such asfibrinogen, prothrombin, tissue thromboplastin, proaccelerin,proconvertin, antihemophilic factor, christmas factor, stuart factor,plasma thromboplastin antecedent (zymogen form of factor XI), Hagemanfactor, fibrin-stabilizing factor, fibrin split products, Fletcherfactor, Fitzgerald factor and von Willebrand factor), cobalamin (vitaminB12), Cocarboxylase, complement system (including C1q, C1r, C1s, C2, C3,factor B (C3 proactivator), C4 (b1E-globulin), C4 binding protein, C5(b1 F-globulin), C6, C7, C8, C9 and properdin), compound S, copper,corticosteroids, corticosterone, cortisol, c-peptide, c-reactiveprotein, creatine, creatinine, cysteine, dehydroepiandrosterone (DHEA),DHEA sulfate, DHEA sulfate, 11-deoxycortisol, dihydrotestosterone (DHT),diphosphoglycerate (phosphate), DNA, dopamine, enzymes, epidermal growthfactor (EGF), epinephrine, ergothioneine, erythrocytes and fragmentsthereof, erythropoietin, estradiol (E2), estriol (E3), estrogen, estrone(E1), fat, free fatty acids, fatty acids, ferritin, alpha-1-fetoprotein,flavin adenine dinucleotide, fluoride, folate, folic acid, fructose,furosemide glucuronide, galactose, gastric inhibitory peptide (GIP),gastrin, globulin, alpha-1-globulin, alpha-2-globulin, beta globulin,gamma globulin, glucagon, glucosamine, glucose, glucuronic acid,glutamic acid, glutamine, glutathione, reduced, glycerol, glycine,glycogen, glycoprotein, cgmp, gonadotropin-releasing hormone, guanidine,haptoglobin, hemoglobin, hexosephosphate p, histamine, histidine,beta-hydroxybutyric acid, 17-hydroxycorticosteroids,17-hydroxyprogesterone, antibodies (including immunoglobulin A,immunoglobulin D, ilmmunoglobulin G, immunoglobulin M and immunoglobulinE), indican, inositol, insulin, insulin-like growth factor, iodine,iron, isoleucine, ketone bodies, alpha-ketonic acids, lactate, lecithin,leptin, leucine, leukocytes and fragments thereof (including neutrophilgranulocytes, neutrophils, eosinophil granulocytes, eosinophils,basophil granulocytes, basophils, lymphocytes, monocytes andphagocytes), lipase p, lipids, lipoproteins, lithium, lysine, lysozyme(muramidase), alpha 2-macroglobulin, magnesium, malic acid, manganese,melatonin, methemoglobin, methionine, methyl guanidine,beta-2-microglobulin, MIP-1a, MIP-1b, mucopolysaccharides, mucoproteins,nerve growth factor (NGF), niacin, norepinephrine, nucleotides,ornithine, oxalate, oxytocin, pancreatic polypeptide, pantothenic acid(vitamin B5), para-aminobenzoic acid, parathyroid hormone (PTH),pentose, phenylalanine, phospholipid, phosphatase, phosphorus, phytanicacid, platelets or fragments thereof, platelet-derived growth factor,polysaccharides, potassium, pregnenolone, progesterone, proinsulin,prolactin, proline, prostaglandin, protein, protoporphyrin, prostatespecific antigen, pseudoglobulin I, pseudoglobulin ii, purine,pyrimidine nucleotides, pyridoxine (vitamin B6), pyruvic acid, RANTES,relaxin, retinol (vitamin A), riboflavin (vitamin B2), RNA, secretin,serine, serotonin (5-hydroxytryptamine), silicon, sodium, somatotropin(growth hormone), sphingomyelin, succinic acid, sulfates, sulfur,taurine, testosterone, thiamine, thiocyanate, threonine, thyroglobulin(Tg), thyroid hormones, thyrotropin-releasing hormone, thyroxine (FT4),thyroxine-binding prealbumin, thyroxine-binding globulin, tin,alpha-tocopherol (vitamin e), transcortin, transferrin, triglycerides,triiodothyronine, tryptophan, tyrosine, urea, uric acid, valine,vasointestinal peptide (vip), vasopressin, zinc and any combinationthereof.

The blood product component may be a growth factor, cytokine, chemokine,hormone, vitamin, or cell fragment.

The growth factor may be selected from the group consisting ofendothelial growth factor (EGF), hepatocyte growth factor (HGF), basicfibroblast growth factor (bFGF), granulocyte colony-stimulating factor(G-CSF), vascular endothelial growth factor (VEGF), transforming growthfactor alpha (TGF-α), TGF-β1, TGF-β2, TGF-β3, platelet-derived growthfactor (PDGF)-AA, PDGF-AB, PDGF-BB, insulin-like growth factor-1(IGF-1), BMP, BDNF, EGF, HGF,PDGF, FGF, PGF, GDF-8, NGF, Epo, TPO, TCGF,IGF-I, IGF-II, KGF, VEGF, and any combination thereof.

The cytokines may be pro-inflammatory or anti-inflammatory.

The proinflammatory cytokine may be for example granulocyte-macrophagecolony-stimulating factor (GM-CSF), interleukin (IL)-1α, IL-1β, IL-2,IL-2R, IL-3, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-12p40/p70,IL-13, IL-14, IL-15, IL-17, tumour necrosis factor (TNF)α, TNF-β,interferon (IFN)-α, INF-β, INF-γ or any combination thereof.

The anti-inflammatory cytokine may be for example IL-1 RA, IL-4, IL-5,IL-10, IL-13, IFNa or any combination thereof.

The chemokine may be eotaxin, protein 10 (IP-10), monocytechemoattractant protein-1 (MCP-1), IFNγ-induced monokine, macrophageinflammatory protein (MIP)-1α, MIP-1β, RANTES or any combinationthereof.

The cytokines may be isolated from the blood product. For example thecytokine

In some embodiments the cytokines are freeze dried or lyophilised. Thesemethods are well known in the art and are commonly used to preserve thefunction of temperature sensitive products, such as enzymes and bloodproducts like cytokines.

The hormone may be selected from the group consisting of an amino acidhormone, eicosanoid hormone, a peptide hormone and a steroid hormone.

The amino acid hormone may be selected from the group consisting ofepinephrine, melatonin, triiodothyronine and thyroxine.

The eicosanoid hormone may be selected from the group consisting ofprostaglandins, leukotrienes, prostacyclin and thromboxane.

The peptide hormone may be selected from the group consisting of amylin,anti-mullerian hormone, adiponectin, angiotensinogen, angiotensin,vasopressin, atrial natriuretic peptide, brain natriuretic peptide,calcitonin, cholecystokin, corticotropin-releasing hormone, cortistatin,encephalin, endothelin, erythropoietin, galanin, gastric inhibitorypeptide, gastrin, ghrelin, glucagon, glucagon-like-peptide-1,gonadotropin-releasing hormone, growth hormone-releasing hormone,hepcidin, human chorionic gonadotropin, human placental lactogen, humangrowth hormone, inhibin, insulin, insulin-like growth factor, leptin,lipotropin, melanocyte stimulating hormone, motilin, orexin, oxytocin,pancreatic polypeptide, parathyroid hormone, pituitary adenylatecyclase-activating peptide, prolactin, prolactin releasing hormone,relaxin, renin, secretin, somatostatin, thrombopoietin,thyroid-stimulating hormone and vasoactive intestinal peptide.

The steroid hormone may be selected from the group consisting oftestosterone, dehydroepiandrosterone, androstenedione,dihydrotestosterone, aldosterone, estradiol, estrone, estriol, cortisol,progesterone, calcitriol and calcidiol.

In some embodiments, each component may be present in an amount fromabout 0.1-1000 pg/ml, about 1-1000 pg/ml, about 50-1000 pg/ml, about100-1000 pg/ml, about 200-1000 pg/ml, about 300-1000 pg/ml, about400-1000 pg/ml, about 500-1000 pg/ml, about 600-1000 pg/ml, about700-1000 pg/ml, about 800-1000 pg/ml, about 900-1000 pg/ml, about 1 -100ng/ml, about 10-100 ng/ml, about 10-100 ng/ml, about 20-100 ng/ml, about30-100 ng/ml, about 40-100 ng/ml, about 50-100 ng/ml, about 60-100ng/ml, about 170-100 ng/ml, about 80-100 ng/ml, about 90-100 ng/ml, orat least about 100 ng/ml.

Transdermal Carriers and Enhancers

The formulation comprises a transdermal carrier facilitates passage ofthe component of the plasma or serum through the skin. Preferably, thetransdermal carrier facilitates passage of the component of the plasmaor serum through the skin and into the circulation to so that thecomponent is administered systemically.

It is to be understood that any suitable transdermal carrier or solventwhich facilitates transdermal absorption of the component may be used.Examples of suitable transdermal carriers include carriers such asisopropyl alcohol, dipropylene glycol methyl-ether, butylatedhydroxytoluene dipropylene glycol monomethyl-ether, 1-methoxy 2-propanol(glysolv PM/Icinol PM), Ethylene glycol monobutylether (butylglyxolv/butyl icinol), Butyl di glysolv (butyl-icinol), Transcutol,propylene glycol (PG), N-methyl-2 pyrrolidone (NMP), methylene chloride,diethyl ether, ethanol, acetonitrile, ethyl acetate, benzyl alcohol, acombination of natural oil; ethylene glycol, propylene glycol, dimethylpolysiloxane (DMPX), oleic acid, caprylic acid, 1-octanol, ethanol(denatured or anhydrous), liposomal compositions, suitable plant oils,such as Aloe vera derivatives or sesame seed oil or derivatives thereof,acrylic polymers, rubber-based polymers, polysiloxane-based polymers,polyvinylpyrrolidone-based polymers, dimethylsulfoxide (DMSO),dimethylformamide (DMF), lecithin, Transfersomes® (IDEA AG).Transfersomes® are artificial vesicles designed to mimic a cell vesicleand deliver component into a cell. The bounding membrane of aTransfersomes® is more flexible than that of a liposome, allowing it todeform and pass through openings in a barrier, such as the skin, whosediameters are much smaller than the average vesicle size. ATransfersome® is a bi-component, most often vesicular, aggregate. Themain functional characteristic of the aggregate is the extremeflexibility and permeability of its bilayer-like membrane coating. Itsbasis is the interdependency of local membrane shape and composition,which makes the bilayer self-regulating and self-optimising. The bilayeris thus capable of stress adaptation, via local and reversible bilayercomponent demixing.

Additional transdermal carriers include, but are not limited to,ethosomes, azone, castor oil derivatives, such as ethoxylated castoroil, jojoba oil derivatives, corn oil derivatives, emu oil derivatives,or any other suitable transdermal or transcutaneous carrier or carriercomposition.

In an embodiment the transdermal carrier is propylene glycol, DMSO, oralcohol.

The transdermal carrier is typically used in an amount of about 1% (w/w)to about 35% (w/w). For example the amount of enhancer used may be about1% (w/w), or about 2% (w/w), or about 3% (w/w), or about 4% (w/w), orabout 5% (w/w), or about 6% (w/w), or about 7% (w/w), or about 8% (w/w),or about 9% (w/w), or about 10% (w/w), or about 11% (w/w), or about 12%(w/w), or about 13% (w/w), or about 14% (w/w), or about 15% (w/w), orabout 16% (w/w), or about 17% (w/w), or about 18% (w/w), or about 19%(w/w), or about 20% (w/w), or about 21% (w/w), or about 22% (w/w), orabout 23% (w/w), or about 24% (w/w), or about 25% (w/w), or about 26%(w/w), or about 27% (w/w), or about 28% (w/w), or about 29% (w/w), orabout 30% (w/w) or about 29% (w/w), or about 30% (w/w),or about 31%(w/w), or about 32% (w/w), or about 33% (w/w), or about 34% (w/w), orabout 35% (w/w), or about 36% (w/w), or about 37% (w/w), or about 38%(w/w), or about 39% (w/w), or about 40% (w/w), or about 41% (w/w), orabout 42% (w/w), or about 43% (w/w), or about 44% (w/w), or about 45%(w/w), or about 46% (w/w), or about 47% (w/w), or about 48% (w/w), orabout 49% (w/w), or about 50% (w/w).

In certain embodiments a transdermal enhancer is incorporated into theformulation. The term “transdermal enhancer” as used herein refers tosubstances used to increase permeability and/or accelerate the deliveryof a component of a blood product through the skin. Enhancers includemonohydric alcohols such as ethyl, isopropyl, butyl and benzyl alcohols;or dihydric alcohols such as ethylene glycol, diethylene glycol, orpropylene glycol dipropylene glycol and trimethylene glycol; orpolyhydric alcohols such as glycerin, sorbitol and polyethylene glycol,which enhance drug solubility; polyethylene glycol ethers of aliphaticalcohols (such as cetyl, lauryl, oleyl and stearyl) includingpolyoxyethylene-4-lauryl ether, polyoxyethylene-2-oleyl ether andpolyoxyethylene-10-oleyl ether; vegetable, animal and fish fats and oilssuch as cotton seed, corn, safflower, olive and castor oils, squalene,and lanolin; fatty acid esters such as propyl oleate, decyl oleate,isopropyl palmitate, glycol palmitate, glycol laurate, dodecylmyristate, isopropyl myristate and glycol stearate which enhance drugdiffusibility; fatty acid alcohols such as oleyl alcohol and itsderivatives; fatty acid amides such as oleamide and its derivatives;urea and urea derivatives such as allantoin which affect the ability ofkeratin to retain moisture; polar solvents such asdimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllaurylamide,dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide,decylmethylsulfoxide and dimethylformamide; salicylic acid; benzylnicotinate; or higher molecular weight aliphatic surfactants such aslauryl sulfate salts, esters of sorbitol and sorbitol anhydride such aspolysorbate. Other suitable enhancers include oleic and linoleic acids,triacetin, ascorbic acid, panthenol, butylated hydroxytoluene,tocopherol, tocopherol acetate, tocopheryl linoleate.

Other suitable transdermal enhancers include alcohols, amino acids,Azone® Azone-like compounds, so called soft penetration enhancers,sulphoxides, essential oils, fatty acids and fatty acid esters,macrophilic compounds, phospholipids and phospholipid derivatives and2-pyrolidone derivatives.

In some embodiments enhancers are incorporated into the formulation inan amount typically up to about 30%. For example the amount of enhancerused may be about 0.05% (w/w), or about 0.1% (w/w), or about 0.5% (w/w),or about 1% (w/w), or about 2% (w/w), or about 3% (w/w), or about 4%(w/w), or about 5% (w/w), or about 6% (w/w), or about 7% (w/w), or about8% (w/w), or about 9% (w/w), or about 10% (w/w), or about 11% (w/w), orabout 12% (w/w), or about 13% (w/w), or about 14% (w/w), or about 15%(w/w), or about 16% (w/w), or about 17% (w/w), or about 18% (w/w), orabout 19% (w/w), or about 20% (w/w), or about 21% (w/w), or about 22%(w/w), or about 23% (w/w), or about 24% (w/w), or about 25% (w/w), orabout 26% (w/w), or about 27% (w/w), or about 28% (w/w), or about 29%(w/w), or about 30% (w/w).

Preparation of the Formulation

In general the formulations are prepared by adding each of thecomponents to the liposomal base and mixing to homogeneity. For examplethe blood product and transdermal enhancer, and any other optionalcomponents such as transdermal enhancers, exogenous cellular extracts,growth factors, hormones, metabolites, or peptides.

In some embodiments the blood product may be concentrated for example byevaporation, ultrafiltration, cross flow filtration or the like beforeaddition to the liposomal base. In other embodiments the blood productmay be fractionated for example by chromatography or precipitation ofdesired components using for example ammonium chloride to select forand/or concentrate desirable components. The concentration processresults in an increased concentration of components such as cytokines,growth factors and chemokines in the blood product that forms part ofthe formulation. As a result of the concentration the blood products andhence the formulations, comprise supra-physiological levels of thecomponents.

During preparation of the formulation at least a portion of the bloodproduct and the transdermal carrier is incorporated into the liposomesof the liposomal base such that at least some of the liposomes containat least a portion of the blood product and the transdermal carrier.

In embodiments where the formulations comprise a transdermal enhancer, aportion of the enhancer may also be present inside the liposome.

In some embodiments the skin care formulation for transdermaladministration of a component of a blood product comprises a bloodproduct and a transdermal carrier, wherein the skin care formulation ispresent in an oral dosage form selected from the group consisting on ofa sublingual troche, tablet, wafer or lozenge. In some embodiments thedosage form is a buccal troche, tablet, wafer, lozenge or orallydisintegrating tablet.

In some embodiments the oral dosage form is solid at room temperature.Preferably the oral dosage form at least partially dissolves at bodytemperature within the mouth of a user.

The oral dosage form (e.g. sublingual troche) troche can be preparedusing any method known in the art. For example the sublingual troche maybe prepared by combining low molecular weight polyethylene glycol (forexample with molecular weights of 1300 to 1650 g/mol) with gum acacia,citric acid, a sweetener such as stevia extract powder, and a flavoringsuch as peppermint oil with the blood product. Preferably the bloodproduct is lyophilized. For example the blood product can be freezedried plasma from typed and/or cross matched donors.

In some embodiments the oral dosage form further comprises a transdermalenhancer.

Methods

The formulations and dosage forms described herein can be used to treat,prevent or ameliorate at least one symptom or sign of a skin defect, forexample by facilitation the transdermal delivery of a blood product. Themethods typically comprise topical administration of the formulation toat least a portion of the skin of a subject having a skin defect in anamount sufficient to treat, prevent or ameliorate at least one symptomor sign the skin defect. In some embodiments the methods compriseadministration of a component of a blood product using an oral dosageform selected from a sublingual troche, tablet, wafer or lozenge. Insome embodiments the oral dosage form is a buccal troche, tablet, wafer,lozenge or orally disintegrating tablet.

In other embodiments the formulation is administered to the nasal mucosafor example using a nasal applicator.

There is also provided a method of improving the quality of hair. Inthis embodiment the method includes the step of topically applying theformulation to an area of skin, for example, on the head, that hasthinning hair or where hair is absent. It is believed that the bloodproducts in the formulations contain components that assist in thereversal of hair follicle deterioration and are thereby useful inimproving the quality of hair.

The formulations may also include extracts from natural mediums such asplacenta extracts, extracts from Wharton's jelly, or amniotic fluids orcomponents extracted from these tissues, or cord blood plasma, cordblood serum or components derived from them.

The formulation is preferably applied more than once. For example theformulation may be applied daily, twice daily, three times or more thanthree times daily. Application of the formula may be continued until theskin defect is resolved or prevented or until at least one symptom orsign of the skin defect is ameliorated. For example the formulation maybe applied over a period of one week, two weeks, three weeks, fourweeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, tenweeks, twelve weeks or longer.

In some embodiments application of the formulation provides positiveeffects on skin defects and in some cases assists in the repair of theskin defects. Application of the formulation may have a soothing effect.

Application of the formulation may also prevent or reduce scarformation. For example the formulation may interfere with scar formingproteolytic enzymes (such as tryptase and chymase) or stimulate theinhibition of leucocytic elastatse to block mast cell activity.

Formulations for reducing or preventing scar formation may additionallycontain hyaluronic acid (HA) or a salt thereof.

Application of the formulation can also enhance the functional capacityof skin, enhance secretion of growth factors in the skin, enhancecirculation to enhance skin regeneration, viability and/or elasticity.The formulations may also improve moisture uptake and retention in theskin by protecting against hypertonic and hypotonic stress, desiccationand dehydration, providing a barrier to inhibit tissue and moistureloss, progressively hydrating the different layers of the skin andsoftening hard tissue.

Application of the formulation may enhance repair and reconstruction ofthe extracellular matrix and normal skin architecture, mitogenicactivity, procollagen production, collagen production.

It is known that Young's modulus of the skin increases linearly withage. Young's modulus (or the elastic modulus) is a measure of stiffnessand defines the relationship between stress (force per unit area) andstrain (proportional deformation) in a material. Specifically, Young'smodulus is the ratio of stress (pressure) to strain (which isdimensionless). Accordingly, Young's modulus has units of pressure, i.e.pascals or N/m² or kg·m⁻¹·s⁻²). A high Young's modulus indicates thatthe material is inelastic and a low Young's modulus indicates that thematerial is elastic. For example rubber has an approximate Young'smodulus of 0.01-0.1 MPa and concrete has an approximate Young's modulusof 30 GPa. Human skin has a Young's modulus of between 0.42 MPa and 0.85MPa.

Young's modulus of skin can be measured by any method known in the artincluding Optical Coherence Elastography (OCE), mechanical stretchingand suction tests.

Application of the formulations described herein results in a reductionof Young's modulus. For example application of the treatment can resultin a reduction of the Young's modulus by up to about 50% compared to theskin before treatment. For example the reduction may be about 5%, about10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,about 45% or about 50%.

Application of the formulation also reduces the number of visible finelines and wrinkles. For example the number of visible fine lines may bereduced at least 50% compared to the skin before treatment. Thereduction may be about 5%, about 10%, about 15%, about 20%, about 25%,about 30%, about 35%, about 40%, about 45% or at least about 50%.Similarly the number of wrinkles may be reduced by at least 50% comparedto the skin before treatment. The reduction may be about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45% or at least 50%.

Skin Defects

The formulation are useful to treat, prevent or ameliorate at least onesymptom or sign of a skin defect.

The skin defect may be a scar, a cosmetic skin defect, a traumatic skindefect, a chronic defect, a scar resulting from non-surgical/accidentaltrauma, a scar resulting from surgical trauma, a scar resulting from achronic disease state, a scar resulting from topical irritation,depleted collagen levels, depleted elastin levels, depleted adhesiveplaques at the dermal/epidermal junction, damage caused by age-relatedskin deterioration, collagen mis-alignment, scarring, scar formation,stretch marks, keloids, diabetic neuropathies, hardened-cracked skin,hardened cracked heel tissue, fine lines, wrinkles, or skin sagging.

The skin defect may also be poor skin texture, wrinkles, UV induced skindamage, skin aging, dry skin, dermatitis, eczema, rash, pruritus, sunburn, burns, stretch marks, acne scars, surgical scars.

In other embodiments the skin defect may be hair follicle deteriorationor alopecia,

Kits

In one embodiment, a kit is provided including a formulation asdescribed herein; a container; a label; and instructions which providemethods of applying the formulation. The instructions may be a pamphlet,CD, or other computer readable medium. Further, the instructions mayprovide information about a website which may contain downloadablecontent.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notrestrictive.

In order that the present invention may be more clearly understood,preferred embodiments will be described with reference to the followingdrawings and examples.

EXAMPLE 1 Plasma Formulation

Exemplary Plasma Formulation Human plasma or plasma lysate: 10 mlPropylene Glycol 10 gm Liposomal base PCCA Lipoderm ® q.s. 80 gm

EXAMPLE 2 Serum Formulation

Exemplary Serum Formulation Human serum 10 ml Propylene Glycol 10 gmLiposomal base PCCA Lipoderm ® q.s. 80 gm

EXAMPLE 3 PRP Formulation

Exemplary Serum Formulation Human PRP (platelet rich plasma) 10 mlPropylene Glycol 10 gm Liposomal base PCCA Lipoderm ® q.s. 80 gm

EXAMPLE 4 ACS Formulation

Exemplary Serum Formulation Human Autologous conditioned serum 10 mlPropylene Glycol 10 gm Liposomal base PCCA Lipoderm ® q.s. 80 gm

EXAMPLE 5 Manufacturing Method

Each of the formulations is prepared using the following generalprocedure

Weigh Lipoderm (gel or cream) in a suitable container.

Transfer blood product (serum, plasma, PRP, ACS etc) under asepticconditions to the Lidoderm.

Add additives such as hyaluronic acid, vitamins, antioxidants,transdermal carriers or enhancers.

Mix components with gentle agitation.

Seal the container and allow air to diffuse out of the gel.

Fill into appropriate tub or airless container. Check pH.

Typically the formulation will have a pH from 6.0 to 7.0.

EXAMPLE 6 Skin Rejuvenation

Subjects of good general health and with visible fine or deep wrinklesin the face, were chosen. Subjects with a history of, or active, skindisease were excluded. Subjects were asked to stop their current regimeof skin care products. Make-up and sunscreens were permitted.

Treatment Regimen

The plasma formulation of Example 1 was applied in mornings and eveningsto the facial skin for 6 weeks. A treatment group of 5 subjects wereasked to document each application of the formulation. A second groupwas asked to apply a placebo comprising only the lipodermal base (PCCALipoderm®) according to the same treatment regimen.

Results

Subjects were evaluated by a visual assessment of skin quality prior tocommencement of the treatment and again after the treatment wascomplete. Compared to the baseline observations all subjects in thetreatment group had significant improvement in texture with the skinfeeling firmer and more elastic. There was also a reduction in thenumber of visible fine lines and wrinkles. In comparison all subjects inthe placebo group had no change in skin texture or in the number ofvisible fine lines and wrinkles compared to baseline observations.

The number of visible fine lines were reduced by 30% compared to theskin before treatment. Similarly the number of visible wrinkles werereduced by 30% compared to the skin before treatment.

All subjects liked the way the formulation felt and indicated that theywould continue its regular use after the study period.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the technology as shownin the specific embodiments without departing from the spirit or scopeof technology as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notrestrictive.

1. A skin care formulation for transdermal administration of a componentof a blood product, the formulation comprising: a blood product; atransdermal carrier; and a liposomal base; wherein at least a portion ofthe blood product and transdermal carrier is contained within liposomesof the liposomal base.
 2. The formulation of claim 1 in a nasal dosageform or an oral dosage form selected from the group consisting of asublingual troche, tablet, wafer, lozenge, buccal troche, tablet, wafer,lozenge, and orally disintegrating tablet.
 3. The formulation of claim 1wherein the blood product is selected from the group consisting ofplasma, serum, platelet rich plasma, conditioned plasma and combinationsthereof.
 4. The formulation of claim 3 wherein the blood product is ahuman blood product.
 5. The formulation of claim 1 wherein the bloodproduct is present in an amount of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 19%, 20%, 21%, 22%, 23%, 24%,25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%,39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%,53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%,67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80%.6. The formulation of claim 1 wherein the blood product includes acomponent selected from the group consisting of growth factor, cytokine,hormone, vitamin, cell, cell fragment, and combination thereof.
 7. Theformulation of claim 6 wherein the growth factor is selected from thegroup consisting of endothelial growth factor (EGF), hepatocyte growthfactor (HGF), basic fibroblast growth factor (bFGF), granulocytecolony-stimulating factor (G-CSF), vascular endothelial growth factor(VEGF), transforming growth factor alpha (TGF-α), TGF-β1, TGF-β2,TGF-β3, platelet-derived growth factor (PDGF)-AA, PDGF-AB, PDGF-BB,insulin-like growth factor-1 (IGF-1), BMP, BDNF, EGF, HGF,PDGF, FGF,PGF, GDF-8, NGF, Epo, TPO, TCGF, IGF-I, IGF-II, KGF, VEGF, and anycombination thereof.
 8. The formulation of claim 6 wherein the cytokineis selected from the group consisting of granulocyte-macrophagecolony-stimulating factor (GM-CSF), interleukin (IL)-1α, IL-1β, IL-2,IL-2R, IL-3, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-12,p40/p70, IL-13, IL-14, IL-15, IL-17, tumour necrosis factor (TNF)α,TNF-β, interferon (IFN)-α, INF-β, INF-γ, IL-1RA, IL-4, IL-5, IL-10,IL-13, IFNα, and any combination thereof.
 9. The formulation of claim 6wherein the hormone is selected from the group consisting ofepinephrine, melatonin, triiodothyronine, thyroxine, prostaglandin,leukotriene, prostacyclin, thromboxane, amylin, anti-mullerian hormone,adiponectin, angiotensinogen, angiotensin, vasopressin, atrialnatriuretic peptide, brain natriuretic peptide, calcitonin,cholecystokin, corticotropin-releasing hormone, cortistatin, encephalin,endothelin, erythropoietin, galanin, gastric inhibitory peptide,gastrin, ghrelin, glucagon, glucagon-like-peptide-1,Gonadotropin-releasing hormone, Growth hormone-releasing hormone,hepcidin, human chorionic gonadotropin, human placental lactogen, humangrowth hormone, Inhibin, Insulin, Insulin-like growth factor, leptin,lipotropin, melanocyte stimulating hormone, motilin, orexin, oxytocin,pancreatic polypeptide, parathyroid hormone, pituitary adenylatecyclase-activating peptide, prolactin, prolactin releasing hormone,relaxin, renin, secretin, somatostatin, thrombopoietin,thyroid-stimulating hormone, vasoactive intestinal peptide,testosterone, dehydroepiandrosterone, androstenedione,dihydrotestosterone, aldosterone, estradiol, estrone, estriol, cortisol,progesterone, calcitriol, calcidiol, and any combination thereof. 10.The formulation of claim 6 wherein the component is present in an amountfrom about 0.1-1000 pg/ml, about 1-1000 pg/ml, about 50-1000 pg/ml,about 100-1000 pg/ml, about 200-1000 pg/ml, about 300-1000 pg/ml, about400-1000 pg/ml, about 500-1000 pg/ml, about 600-1000 pg/ml, about700-1000 pg/mL, about 800-1000 pg/mL, about 900-1000 pg/mL, about 1 -100ng/ml, about 10-100 ng/ml, about 10-100 ng/ml, about 20-100 ng/ml, about30-100 ng/ml, about 40-100 ng/ml, about 50-100 ng/ml, about 60-100ng/ml, about 170-100 ng/ml, about 80-100 ng/ml, about 90-100 ng/ml, orat least about 100 ng/ml.
 11. The formulation of claim 1 wherein theblood product is lyophilized or freeze-dried.
 12. The formulation ofclaim 1 wherein the transdermal carrier is selected from the groupconsisting of isopropyl alcohol, dipropylene glycol methyl-ether,butylated hydroxytoluene dipropylene glycol monomethyl-ether, 1-methoxy2-propanol (glysolv PM/Icinol PM), Ethylene glycol monobutylether (butylglyxolv/butyl icinol), Butyl di glysolv (butyl-icinol), Transcutol,propylene glycol (PG), N-methyl-2 pyrrolidone (NMP), methylene chloride,diethyl ether, ethanol, acetonitrile, ethyl acetate, benzyl alcohol, acombination of natural oil; ethylene glycol, propylene glycol, dimethylpolysiloxane (DMPX), oleic acid, caprylic acid, 1-octanol, ethanol(denatured or anhydrous), liposomal compositions, suitable plant oils,such as Aloe vera derivatives or sesame seed oil or derivatives thereof,acrylic polymers, rubber-based polymers, polysiloxane-based polymers,polyvinylpyrrolidone-based polymers, dimethylsulfoxide (DMSO),dimethylformamide (DMF), lecithin, vesicular aggregates, ethosomes,azone, castor oil derivatives, such as ethoxylated castor oil, jojobaoil derivatives, corn oil derivatives, propylene glycol, and emu oilderivatives.
 13. The formulation of claim 1 wherein the transdermalcarrier is present in an amount of 1% (w/w) 2% (w/w), 3% (w/w), 4%(w/w), 5% (w/w), or 6%, 7% (w/w), 8% (w/w), 9% (w/w), 10% (w/w), 11%(w/w), 12% (w/w), 13% (w/w), 14% (w/w), 15% (w/w), 16% (w/w), 17% (w/w),18% (w/w), 19% (w/w), 20% (w/w), 21% (w/w), 22% (w/w), 23% (w/w), 24%(w/w), 25% (w/w), 26% (w/w), 27% (w/w), 28% (w/w), 29% (w/w), 30% (w/w),29% (w/w), 30% (w/w), 31% (w/w), 32% (w/w), 33% (w/w), 34% (w/w), 35%(w/w), 36% (w/w), 37% (w/w), 38% (w/w), 39% (w/w), 40% (w/w), 41% (w/w),42% (w/w), 43% (w/w), 44% (w/w), 45% (w/w), 46% (w/w), 47% (w/w), 48%(w/w), 49% (w/w), or 50% (w/w).
 14. The formulation of claim 1 whereinthe liposomal base is a mixture of about 60-80% wt/wt water, glycerin,C₁₂₋₁₅ alkyl benzoate, glyceryl stearate, dimethicone, cetearyl alcohol,cetearyl glucoside, polyacrylamide, cetyl alcohol, magnesium aluminumsilicate, xanthan gum, aloe vera, tocopheryl acetate, prunus amygadalusamara kernel oil, vitis vinifera seed extract, triticum vulgare germoil, retinyl palmitate, ascorbyl palmitate, Pro-Lipo Multi-emulsionLiposomic System, tetrasodium EDTA, phenoxyethanol, and sodiumhydroxymethylglycinate.
 15. The formulation of claim 1 furthercomprising a transdermal enhancer selected from the group consisting ofethyl alcohol, isopropyl alcohol, butyl alcohol, benzyl alcohol,ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycoltrimethylene glycol, glycerin, sorbitol, polyethylene glycol,polyoxyethylene-4-lauryl ether, polyoxyethylene-2-oleyl ether,polyoxyethylene-10-oleylether, cotton seed oil, corn oil, safflower oil,olive oil, castor oil, squalene, lanolin; propyl oleate, decyl oleate,isopropyl palmitate, glycol palmitate, glycol laurate, dodecylmyristate, isopropyl myristate, glycol stearate, oleyl alcohol,oleamide, dimethyldecylphosphoxide, methyloctylsulfoxide,dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide,dimethylsulfoxide, decylmethylsulfoxide, dimethylformamide; salicylicacid; benzyl nicotinate; lauryl sulfate, sorbitol, polysorbate, linoleicacid, triacetin, ascorbic acid, panthenol, butylated hydroxytoluene,tocopherol, tocopherol acetate, and tocopheryl linoleate.
 16. Theformulation of claim 1 comprising: 1 to 80% (v/w) of the blood product;1% to 50% (w/w) of the transdermal carrier; and up to 80% (w/w) of theliposomal base.
 17. The formulation of claim 16 wherein the bloodproduct is human plasma or plasma lysate, human serum, human PRP(platelet rich plasma), or human autologous conditioned serum; and thetransdermal carrier is propylene glycol.
 18. A method of treating,preventing or ameliorating a symptom or sign of a skin defect, themethod comprising administering to the skin of a subject in need thereofa formulation of claim 1 in an amount sufficient to treat, prevent orameliorate a symptom or sign of the skin defect.
 19. The method of claim18 wherein the skin defect is selected from the group consisting of poorskin texture, wrinkles, fine lines, UV induced skin damage, skin aging,dry skin, hair follicle deterioration, alopecia, dermatitis, eczema,rash, pruritus, sun burn, burns, stretch marks, acne scars, and surgicalscars.
 20. The method of claim 19 wherein the skin defect is wrinkles orfine lines and the treatment reduces the number of wrinkles or finelines by up to 5% compared to the number of wrinkles or fine linesbefore treatment.